The Retina and Retinal Diseases: The retina is the layer of nerve cells at the back of the eye, which convert light into nerve signals that are sent to the brain. In humans, and in other primates (but not in most other mammals, or other types of animals), the retina has a small yellowish area in the center of the field of vision. That yellowish area is called the “macula.” It provides fine resolution vision in the center of the visual field and is essential to good vision. People who suffer from macular degeneration often lose the ability to read, recognize faces, drive, or walk safely on unfamiliar routes.
The surrounding portions of the macula can only provide coarse resolution. This physiological feature limits and controls the number of nerve signals that the brain must rapidly process, to form coherent rapid-response vision, and it also helps limit and control the huge number of rod and cone receptors that the eye must continually regenerate and recycle, every day. Many people do not realize the retina can provide only coarse resolution, outside of a limited central area, because the eyes and the brain have developed an extraordinary ability to synthesize coherent vision from a combination of fine and coarse resolution. During that type of vision synthesis, the eye muscles cause the eyes to flit back and forth over a larger field of vision, pausing at each location for just an instant while the eye quickly “grabs” a fine-resolution image of a limited area. This process occurs so rapidly that a person does not notice it happening, and does not pay attention to how a complete visual image and impression is being assembled and updated from combinations of fine and coarse resolution images.
There is also a peculiar anatomic structure in the retinas of humans, which points out the difference between fine resolution (provided by the macula) and coarse resolution (provided by the remainder of the retina). In humans, the blood vessels that serve the retina actually sit in front of the retina, where they can block and interfere with incoming light, before the light reaches the retina. This is counter-intuitive, and one should wonder why the retina evolved with a physical handicap that literally gets in the way of good, clear vision. The answer is, in those parts of the retina, only coarse vision is being created, and blood vessels positioned in front of the retina do not interfere with that type of coarse vision. By contrast, in the macular region in the center of the retina, the blood vessels in front of the retina are lacking and supply is only from blood vessels present anywhere behind the layer of neurons with rod and cone receptors. This is consistent with the macula providing fine resolution vision, which would be blocked and hindered if the blood vessels were located in front of the neurons, in ways that would intercept and blocking portions of the incoming light.
“Retinal degeneration” is a descriptive term, which refers to and includes an entire class of eye diseases and disorders. It includes any progressive disorder or disease that causes the macula to gradually degenerate, to a point that substantially impairs or damages eyesight and vision. Several major categories of retinal degeneration are known. These include: (i) age-related macular degeneration, which gradually appears among some people over the age of about 65; (ii) diabetic retinopathy, in which problems with sugar and energy metabolism damage the entire retina, including the macula; (iii) eye diseases that affect the macula due to gene and/or enzyme defects, such as Stargardt's disease, Best's disease, Batten's disease, Sjogren-Larsson syndrome, and various other eye disorders that lead to gradual degeneration of the macula (and possibly other parts of the retina) over a span of time. This is not an exclusive list, and other subclasses and categories also are known. For example, age-related macular degeneration is subdivided into wet and dry forms, depending on whether abnormal and disruptive blood vessel growth is occurring in the structural layers behind the retina.
The causes and effects of macular degeneration, and efforts to prevent or treat it, are described in numerous books (e.g., “Macular Degeneration,” by Robert D'Amato et al (2000) and “Age-Related Macular Degeneration,” by Jennifer Lim (2002)), articles (“Age-Related Macular Degeneration” by Berger et al (1999)) and patents, such as U.S. Pat. No. Re. 38,009, which is assigned to ZeaVision LLC, and is incorporated by reference in its entirety.
In recent years, awareness has grown, among some researchers but not among the general public, of the roles that macular pigment plays, in the health and longevity of the macula. Therefore, the two carotenoid pigments that create and provide the macular pigment are discussed below.
The Macular Pigments: Zeaxanthin and Lutein: The macula has a yellowish color because it contains unusually high concentrations of two specific pigments, called zeaxanthin and lutein. Both are carotenoids, similar to beta-carotene but with hydroxyl groups coupled to their end rings (the presence of one or more oxygen atoms causes a carotenoid to be categorized as a “xanthophyll”, so zeaxanthin and lutein are sometimes referred to as xanthophylls). Both of those two carotenoids are known to be protective and beneficial, in human retinas, by mechanisms that include: (1) absorption of destructive ultraviolet photons; and (2) quenching of destructive radicals. Both of those mechanisms, and other potential protective mechanisms, are discussed below.
In addition to their involvement in the macula and macular degeneration, zeaxanthin and lutein also are present in other eye structures (including the eye lens), and undesirably low levels of those two carotenoids appear to be correlated with higher risks of disorders such as cataracts. Accordingly, although the discussion herein focuses on macular degeneration, it should be recognized that any comments herein about macular pigment levels also have varying degrees of relevance to some other eye disorders as well. Similarly, any comments herein about macular degeneration should be recognized as including disorders that are referred to by other names (such as diabetic retinopathy, Stargardt's disease, etc.), but that involve or lead to gradual deterioration of the macula.
The structures of zeaxanthin and lutein are very similar because they are isomers of each other, differing only in the placement of a double bond in one end ring. In lutein, the ring with a “misplaced” double bond is called an “epsilon” ring. All of the other end rings have “beta” ring structures, which refer to the sequence of double bonds found in beta carotene's two end rings.
However, that single minor structural difference, between zeaxanthin versus lutein, has profound effects on the traits, performance, and tissue concentrations of those two different molecules, in both plants and animals. Briefly, the lutein molecule has a bend where the epsilon ring joins the “straight chain” segment between the two end rings. That bend, near one end, allows lutein to fit properly into ring-shaped “light-harvesting” structures, in the chloroplasts of plant cells. Since light-harvesting (which is part of photosynthesis) is crucial in plants, lutein evolved as a major and dominant carotenoid, in essentially all plants.
By contrast, zeaxanthin does not have a bend at either end. Since it is relatively straight, it cannot fit properly into the circular light-harvesting structures that help carry out photosynthesis, in plants. Therefore, it evolved in plants in ways that led to a very different role in a day-night cycle, in which zeaxanthin and a similar carotenoid called violaxanthin are converted back and forth into each other. As a result, zeaxanthin does not accumulate in substantial quantities in most types of plants (although a few exceptions are known, such as corn and red peppers). Even in dark green plants, such as spinach or kale, lutein content is dozens or even hundreds of times greater than zeaxanthin content. On an aggregate basis, the total amount of zeaxanthin in typical diets in industrial nations is believed to be about 1% (or possibly even less) of the total lutein supply.
Another important difference between zeaxanthin and lutein is that zeaxanthin has a longer and more protective “conjugated cloud” of electrons surrounding it, compared to lutein. When a series of carbon atoms are bonded to each other by alternating double and single bonds, the electrons become mobile, and are no longer affixed to specific bond locations. Those electrons form a flexible and movable electron “cloud”. This same type of cloud also appears in benzene rings and other “aromatic” organic compounds, and it is well-known to chemists.
That type of flexible and movable electron cloud is ideally suited for absorbing high-energy radiation (in the ultraviolet, near-ultraviolet, and deep blue part of the spectrum), without suffering damage or breakage of the molecule. In addition, a flexible and movable electron cloud is ideally suited for neutralizing and “quenching” oxygen radicals, which are aggressively unstable and destructive molecules, containing oxygen atoms having unpaired electrons. Oxidative radicals are important damaging agents in any cells and tissues that are being bombarded by high levels of UV radiation, since UV radiation often breaks bonds that involve oxygen atoms, in ways that create unpaired electrons where the broken bonds previously existed.
All carotenoids are assembled, in plants, from a 5-carbon precursor called isoprene, which has two double bonds separated by a single bond. As a result, all carotenoids have at least some sequence of alternating double and single bonds, leading to a conjugated electron cloud covering at least part of the carotenoid molecule. This is a basic and shared trait of all carotenoids, and it explains how carotenoids provide two crucial benefits (i.e., absorption of UV radiation, and quenching of destructive radicals) that are vital to plants, which must often sit in direct sunlight for hours each day.
However, different carotenoids have conjugated electron clouds that different lengths, and different potencies and protective traits. In particular, there is a crucial difference between the conjugated electron clouds of zeaxanthin and lutein. The placement of the double bonds in both of zeaxanthin's two end rings continues and extends the pattern of alternating double and single bonds, from the straight chain. This extends zeaxanthin's conjugated and protective electron cloud, out over a part of both of zeaxanthin's two end rings.
By contrast, the position of the double bond in lutein's “epsilon” ring disrupts the alternating double/single bond sequence, established by the straight-chain portion of the molecule. This disrupts and terminates the conjugated electron cloud, and it prevents the protective, UV-absorbing, radical-quenching electron cloud from covering any part of lutein's epsilon end ring. That structural difference in their end rings becomes highly important, because zeaxanthin and lutein are deposited into animal cells in ways that cause them to “span” or “straddle” the outer membranes of the cells. It causes zeaxanthin and lutein to be deposited into animal cell membranes in a way that places them perpendicular to the surfaces of the membrane that surrounds and encloses a cell.
It is not fully known, at a molecular level, how lutein's lack of symmetry, and lack of a protective conjugated electron cloud over one end ring, affect its deposition in cells in the human macula. For example, it is not known whether the protective beta rings at one end of lutein are consistently or predominantly placed on either the external or internal surfaces of cell membranes. In addition, it is not known whether lutein is consistently deposited, into human cell membranes, in a membrane-spanning orientation.
However, other aspects of zeaxanthin and lutein content and deposition in blood, and in the macular regions of human retinas, are well-known. Despite the rarity of zeaxanthin in food sources (as mentioned above, zeaxanthin content in typical diets is believed to be less than about 1% of the lutein supply), zeaxanthin concentrations in human blood average about 20% of lutein levels. This clearly indicates that the human body does something that indicates a selective preference for zeaxanthin, over lutein.
Even more revealingly, zeaxanthin is even more concentrated in the crucially important center of the human macula, which provides fine-resolution vision in humans. In the crucially important center of a healthy human macula, zeaxanthin is present at levels that average more than twice the concentrations of lutein. By contrast, lutein is present in higher levels around the less-important periphery of the macula. While the mechanisms which create that pattern of deposition are not fully understood, it recently has been reported that certain enzymes that appear to be involved will clearly bind to zeaxanthin with relatively high affinity under in vitro conditions; however, those same enzymes will not bind to lutein with any substantial affinity (Bhosale et al 2004).
Accordingly, these differences in how zeaxanthin and lutein are deposited in the macula provide strong evidence that the macula wants and needs zeaxanthin, more than lutein. The patterns of deposition, and the known structural and electron cloud differences, suggest and indicate that the macula wants and needs zeaxanthin, and it uses lutein only if and when it cannot get enough zeaxanthin.
This belief is also supported by another important finding. The macula may attempt to convert lutein into zeaxanthin. However, the conversion process cannot convert lutein into the normal stereoisomer of zeaxanthin found in plants and in the diet (the 3R,3′R stereoisomer). Instead, it converts lutein into a different stereoisomer that has never been found in any food sources or mammalian blood. That non-dietary isomer has one end ring with the conventional “R” configuration; however, the second end ring has an unnatural “S” configuration that is never found in the normal diet. That S-R isomer (and R-S isomer) is called meso-zeaxanthin.
Consequently, while lutein may have benefits, a growing body of knowledge and evidence indicates that zeaxanthin is the ideal carotenoid for helping prevent and treat the class of eye diseases that fall into the category of retinal degeneration.
Measuring Macular Pigment: One method of measuring a patient's macular pigment is objective fundus reflectometry or densitometry. This method involves illuminating the retina with a known spectral signature illuminant and collecting and measuring the spectral return light with a variety of detectors. The returned spectral signature, or the luminance as a function of wavelength, can be used to deduce much about a patient's eye health. One use has been to measure the macular pigments in the immediate surrounds of the fovea centralis. It is these pigments that may give an indication of the level of natural protection given to the cones against harmful blue light. In particular, zeaxanthin and lutein are responsible for much of the absorption of the macular pigment. In many macular pigment density measurement schemes, these are measured collective and reported as macular pigment optical density.
U.S. Pat. No. 7,467,870 discloses a macular pigment reflectometer that can measure and report the optical density contributions of zeaxanthin and lutein separately. The macular pigment reflectometer disclosed in the '870 patent is typically a table-mounted instrument that may permit a patient to self-align the instrument for accurate measurement. Once alignment is achieved, the operator of the macular pigment reflectometer conducts the data collection process.
It has generally been challenging to align precision ophthalmic instruments to the human eye. It has been particularly challenging to align an instrument in order to visualize one particular feature of the eye such as the fovea. Handheld instruments are even more difficult to align because the patient, clinician and instrument are in simultaneous asynchronous motion. For alignment, light must get from the instrument, through the eye, to the pupil, and on through the posterior chamber to the retina and back out to the instrument and on to a detector of some nature.
Examples of ophthalmic instruments that have been traditionally difficult to align include ophthalmic fundus cameras such as the Nidek AFC 230/210 fundus camera, macular pigment reflect meters, and optical coherence tomographers. Instrument designers of these instruments have attempted to solve alignment challenges in a number of ways. This includes changing the field of view and working distance in order to present both an anterior and posterior field of view to a detector. This involves interchanging a group of optics to provide for the two fields of view which could be switched at will. One drawback to this approach is that the instrument is large and bulky because two groups of optics are required. Another drawback is the cost of these instruments and that the transition time is a function of how fast the instrument or operator can move and then stabilize these groups of optics.
Another approach has been to design the instrument with two simultaneous viewing channels in which either or both viewing channel could be coupled to one or more imaging detectors. This approach eliminates the transition time issue present in the moving optics approach. However, this approach is problematic because the optics are not arranged in a spatially efficient approach, resulting in a bulky instrument that is difficult to operate. Neither this approach nor the previously described approach is well suited to the needs of a handheld instrument in which bulk, speed, and ease of use are important.
The present invention overcomes these problems by providing a handheld macular pigment reflectometer that is a self-contained system, reduces the errors associated with the motion of typical handheld devices, can operate in dark or illuminated rooms, and includes an enhanced alignment feature.